The SACS gene (Sacsin Molecular Chaperone) encodes a very large multidomain protein involved in protein quality control and mitochondrial dynamics. Mutations cause autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disorder with cerebellar ataxia and spasticity.
The SACS gene is located on chromosome 13q12.12 and encodes sacsin, one of the largest proteins in the human genome at approximately 4,579 amino acids (~520 kDa)[1]. Sacsin functions as a molecular chaperone involved in protein folding, mitochondrial quality control, and cytoskeletal dynamics in neurons[2]. Biallelic loss-of-function mutations cause ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay), originally described in the French-Canadian population of Quebec but now recognized worldwide[3]. [1]
| | | [2]
|---|---| [3]
| Gene Symbol | SACS | [4]
| Full Name | Sacsin Molecular Chaperone |
| Chromosomal Location | 13q12.12 |
| NCBI Gene ID | 26278 |
| OMIM | 604490 |
| Ensembl | ENSG00000151835 |
| UniProt | Q9NZJ4 |
| Associated Diseases | ARSACS, early-onset cerebellar ataxia |
Sacsin contains multiple Hsp90-like domains (sacsin repeating regions, SRRs) that confer chaperone function[2]:
Sacsin plays a critical role in mitochondrial dynamics[4]:
Sacsin interacts with the neuronal cytoskeleton[5]:
ARSACS is characterized by the clinical triad[3]:
| Feature | Description |
|---|---|
| Cerebellar ataxia | Progressive gait and limb ataxia, onset typically in early childhood |
| Pyramidal spasticity | Lower limb spasticity with brisk reflexes and extensor plantar responses |
| Peripheral neuropathy | Axonal and demyelinating sensorimotor neuropathy |
| Inheritance | Autosomal recessive |
| Onset | Usually 1-5 years (walking onset); can be later in non-Quebec populations |
| Retinal changes | Thickened retinal nerve fiber layer (prominent myelinated fibers) — pathognomonic |
The primary neuropathological finding in ARSACS is Purkinje cell degeneration in the cerebellum[6]:
ARSACS pathobiology converges with mechanisms in other neurodegenerative diseases[4]:
| Variant | Effect | Population | Phenotype |
|---|---|---|---|
| c.8844delT | Frameshift (p.Ile2949fs) | French-Canadian founder | Classic ARSACS (>90% of Quebec cases) |
| c.7504C>T (R2502X) | Nonsense | Pan-ethnic | Severe early-onset ARSACS |
| c.5254C>T (R1752X) | Nonsense | Various | Classic ARSACS |
| c.2094-2A>G | Splice site | Italian | ARSACS |
| c.12220G>C (D4074H) | Missense | Japanese | Milder late-onset ataxia |
| Various missense | Partial function | Pan-ethnic | Later onset, slower progression |
SACS is broadly expressed with highest levels in the nervous system[1]:
Expression is highest during neuronal differentiation and maturation, consistent with a developmental role[2].
Anderson JF et al. The sacsin repeating region (SRR): a novel Hsp90-related supra-domain associated with neurodegeneration (2010). 2010. ↩︎
Bradshaw TY et al. A reduction in Drp1-mediated fission compromises mitochondrial health in autosomal recessive spastic ataxia of Charlevoix Saguenay (2016). 2016. ↩︎
Duncan EJ et al. Altered organization of the intermediate filament cytoskeleton and relocalization of proteostasis modulators in cells lacking the ataxia protein sacsin (2017). 2017. ↩︎
Bouchard JP et al. [Autosomal recessive spastic ataxia of Charlevoix-Saguenay (1998)](https://doi.org/10.1016/S0960-8966(97). 1998. ↩︎